Transmission of HIV across mucosal tissues involves a complex yet inefficient series of events that are not yet fully understood. The HIV-1 envelope protein (Env) of early-transmitting viruses has been found to present distinct transmission signatures. One such signature involves a reduced number of potential N-linked glycosylation sites, underscoring the importance of post-translational modifications in transmission fitness. Recently, an additional transmission signature has been identified in the signal peptide of Env. This signature involves the over-representation of basic residues at a specific position in the signal peptide. We investigated the potential impact of this signal peptide signature on gp120 glycosylation and antigenicity.
Two recombinant Envs were constructed, one derived from a chronic isolate that lacks the signal peptide signature and a second from a transmitting isolate that includes the signal peptide signature. Chimeric Envs were also constructed in which the two signal peptides were swapped. All four gp120s were probed with glycan-, structure- and interaction-specific probes in a surface plasmon resonance binding assay.
The signature found in the signal peptide of Env influences qualitative aspects of Env glycosylation that in turn affect the structure and antigenicity of Env in a major way. The signal peptide impacts Env’s affinity for DC-SIGN, a lectin receptor expressed on dendritic cells that is believed to be involved in mucosal transmission. Additionally, affinity for the monoclonal antibody 17b, which recognizes the CD4-induced confirmation of Env is also altered.
We conclude that the HIV Env signal peptide is an important determinant of Env processing, folding and antigenicity. These observations may aid in the development of Env based HIV vaccines.